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Discussion

Our main findings were as follows:(1)ESUS and cardioembolism were the most frequent stroke subtypes in RT and HD patients, respectively;(2)the one-year risk of MACE in stroke patients with RT was significantly lower than that in HD patients and as low as that in the non-RRT patients; and(3)the one-year functional outcomes tended to be better in RT patients than in HD patients. While both risk factor management and appropriate antithrombotic therapies are essential at all stages of CKD13), the benefits of targeted therapies may differ in the RT and HD patients, given the substantial disparities in characteristics and outcomes of stroke between them.

Kidney function

Ischemic Stroke Subtype

Our results are consistent with a prior study reporting that 66% of ischemic strokes after RT were cryptogenic and 31% were likely to be embolic strokes4. The underlying mechanisms of ESUS can be classified as cardioembolic and non-cardioembolic15. Although we performed a standardized cardiac workup, latent paroxysmal atrial fibrillation might be a cause of ESUSin RT patients. Another possibility is embolism from subclinical non-stenotic atherosclerotic lesions. The atherosclerotic process is generally accelerated after RT, resulting in thromboembolic events16. Several studies have reported an increase in the prevalence of atherosclerotic wall changes in RT patients7.18).In our study, ipsilateral 30-50% stenosis of the extracranial carotid artery was found in 15% of RT patients, which was comparable to that in HD patients. Additionally, the serum homocysteine levels were significantly higher in the RT patients than in those without a history of RRT, whereas the prevalence of common vascular risk factors(i.e., hypertension, diabetes, or dyslipidemia) was similar. Previous studies demonstrated that an elevated homocysteine concentration was a predictor of increased cardiovascular morbidity or mortality among patients with end-stage kidney disease19,20). High concentrations of homocysteine are known to have deleterious effects on the vascular endothelium through oxidant stress and promote atherosclerosis and thrombus formation21. 22). Moreover, homocysteine showed a predilection towards the promotion of platelet adhesion to endothelial cells and was also associated with higher levels of prothrombotic factors2). Recent studies indicated that ESUS cases result from non-stenotic atherosclerosis, atrial cardiopathy, patent foramen ovale, etc., which are generally regarded as low- to moderate-risk embolic sources 12). We speculated that thrombotic tendency may be enhanced by the presence of hyperhomocysteinemia even in such non-high-risk diseases. The treatments for lowering homocysteine concentrations may have cardiovascular benefits in RT patients, although further studies are needed to verify this.

Cardioembolism was the most common subtype in patients undergoing HD, presumably because of their high prevalence of atrial fibrillation. This is consistent with the report of a previous study), whereas some studies found that small vessel occlusion was the most frequent subtype for those receiving HD6.4). As renal function declines, patients are more likely to develop atrial fibrillation. The prevalence of atrial fibrillation was reported to be particularly high in HD patients, at 7-27%228). Most HD patients experience chronic volume overload and its rapid fluctuation, which can increase the incidence of atrial fibrillation. In addition, the calcification of the cardiac valve by the dysregulation of calcium and phosphate metabolism can cause valvular heart disease, leading to the development of atrial fibrillation. In our study, the 38.5% prevalence of atrial fibrillation in HD patients was the highest among the groups.

Cistanche can treat kidney disease

Vascular Event Risk

RT patients have a higher cardiovascular risk than the general population, since they usually have, in addition to traditional risk factors such as hypertension, diabetes, hyperlipidemia, or smoking, nontraditional cardiovascular risk factors, including adverse metabolic effects of immunosuppression, chronic anemia, hyperhomocysteinemia, chronic inflammation, proteinuria, and chronic allograft nephropathy30. The United States Renal Data Systems reported that the three-year incidence of de novo cerebrovascular events after RT was 6.8%31)Meanwhile, few data are available on the vascular risks in secondary prevention settings. In our study, the one-year MACE risk after stroke was 11.3% in RT patients, which was comparable with that in non-RRT patients(13.1%)and lower than that in HD patients (28.2%). Our patients in the RT group seemed to undergo rigorous preventive treatment during follow-up. Specifically, the usage rates of antiplatelet, anticoagulant, antihypertensive, and lipid-lowering agents were 74%,32%,62%, and 56%, respectively. These appropriate interventions may have lowered the MACE risk in RT patients to the level of the patients with no RRT history.

Kidney function

Functional Prognosis

Although RRT modalities were not independent determinants of functional prognosis, RT patients seemed to show better outcomes than HD patients;22% and 36% were handicapped or dead one year after stroke in RT and HD patients, respectively. To date, few studies have assessed disability after stroke among RT recipients. Toyoda et al. reported that HD was an independent indicator for an mRS of ≥3 at 4 weeks4. The case fatality of stroke in RT patients has been reported to be very high, with a mortality rate of approximately 40% at one year3. 33). The good prognosis in our study may be partly attributed to the different patient backgrounds as well as the improved secondary prevention measures. In addition, the Japanese RT patients showed excellent long-term outcomes with longer survival periods than the non-Japanese RT patients, which could be consistent with our results.

Limitations

First, the sample was relatively small, especially for the RRT groups; thus, our analysis is susceptible to type II error. However, this is inevitable given that stroke after RT is a rare condition. We could not perform extensive multivariable adjustments because of the small number of outcome events. Second, we had no data available on the exact change of blood pressure levels during follow-up, which could affect the vascular outcomes. Third, because of the single-center setting, generalizability is limited. The annual MACE rate of 11.3% in the non-RRT group was higher than that reported in previous clinical trials on general stroke populations330. This may be in part due to our consecutive enrollment of patients regardless of their age, general conditions, or comorbidities, and clinical trials usually select patients whose systemic condition is fair. In addition, patients were included within one week of onset, ensuring that early recurrent events were captured. It is plausible that our patients represent the"real world" stroke cohort rather than those who would be included in clinical trials. Our results should be interpreted with caution and reproduced in larger multicenter studies.

Conclusions

RT patients were more likely to have ESUS and were at a lower risk of recurrent vascular events than HD patients. Our study provides useful information for developing optimal secondary prevention strategies for patients undergoing RT as well as HD.

Acknowledgments

None.

Grant Support 

None.

Conflict of Interest

Dr. Kitagawa reports personal fees from Kyowa Kirin, grants and personal fees from Daiichi Sankyo, grants from Bayer, and grants from Dainihon Sumitomo outside the submitted work. Other authors have nothing to disclose.

Kidney function

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